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Cancer Stem Cells
Article first published online: 5 JUL 2013
Copyright © 2013 AlphaMed Press
Volume 31, Issue 7, pages 1266–1277, July 2013
How to Cite
Manoranjan, B., Wang, X., Hallett, R. M., Venugopal, C., Mack, S. C., McFarlane, N., Nolte, S. M., Scheinemann, K., Gunnarsson, T., Hassell, J. A., Taylor, M. D., Lee, C., Triscott, J., Foster, C. M., Dunham, C., Hawkins, C., Dunn, S. E. and Singh, S. K. (2013), FoxG1 Interacts with Bmi1 to Regulate Self-Renewal and Tumorigenicity of Medulloblastoma Stem Cells. STEM CELLS, 31: 1266–1277. doi: 10.1002/stem.1401
Author contributions: B.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; X.W., R.M.H., and C.V.: conception and design, collection and/or assembly of data, and final approval of manuscript, S.C.M., N.M., S.M.N., C.L., J.T., C.M.F., and C.D.: collection and/or assembly of data and data analysis and interpretation, K.S., J.A.H., M.D.T., and C.H.: data analysis and interpretation; T.G.: provision of study material or patients; S.E.D.: conception and design, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript, S.K.S.: conception and design, data analysis and interpretation, manuscript writing, and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
first published online in STEM CELLS EXPRESS April 17, 2013.
- Issue published online: 5 JUL 2013
- Article first published online: 5 JUL 2013
- Accepted manuscript online: 17 APR 2013 06:22AM EST
- Manuscript Accepted: 20 FEB 2013
- Manuscript Revised: 27 JAN 2013
- Manuscript Received: 29 SEP 2012
- Canadian Institutes of Health Research Vanier Canada Graduate Scholarship
- Neurosurgical Research and Education Foundation and American Association of Neurological surgeons, Pediatric Section
- Ontario Institute for Cancer Research
- McMaster University Department of Surgery
- Brain tumor-initiating cell;
- Stem cells;
Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 (“non-Shh/Wnt MBs”) are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) self-renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting. STEM Cells2013;31:1266–1277